Objective To investigate the pancreatic tissue injury induced by exenatide in rats. Methods Thirty SD rats were randomly divided into exenatide-induced group and blank control group, with 15 rats in each group. Rats in exenatide-induced group were subcutaneously injected with exenatide at the dose of 5 μg/kg twice a day for 10 weeks, and those in blank control group were injected with the same amount of normal saline. Rats were then sacrificed, blood samples were obtained from inferior vena, and pancreatic tissues were harvested. Serum levels of amylase, lipase, interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α and contents of myeloperoxidase (MPO) in pancreatic tissues were measured by ELISA, pancreatic wet/dry ratios were calculated, HE staining and histopathological scoring of pancreatic tissues were performed, and microstructure of pancreatic tissues were observed by electron microscopy. Results There was no significant difference in serum levels of amylase, lipase, IL-1, IL-6 and TNF-α between two groups （P>0.05）. The content of MOP in exenatide-induced group was significantly higher than that in blank control group [（0.24±0.07）U/L vs （0.18±0.05）U/L]（P<0.05）, and the pancreatic wet /dry ratio in exenatide-induced group was significantly lower than that in blank control group (0.183±0.049 vs 0.256±0.064) （P<0.05）. HE staining demonstrated that there were 5 pancreatic tissue samples with chronic inflammation in exenatide-induced group, while there were no chronic inflammatory changes in blank control group. Histopathological scoring of pancreatic tissues revealed that except for the parameter of gland atrophy, there were significant differences in the parameters of lesion area, fibrosis, inflammation and edema between two groups （P<0.05）. It was observed by electronic microscopy that there were karyopyknosis, cytoplasmic vacuolization, wide intercellular gap and infiltration of inflammatory cells for pancreatic acinar cells in exenatide-induced group, while there was no obvious abnormality in blank control group. Conclusion Long-term administration of exenatide may lead to chronic pancreatic inflammation and pancreatic tissue injury in rats.